This invention relates to a new and practical process for preparing esters of .alpha.,.alpha.-haloalkyl boronic acids. More particularly, the invention relates to the preparation of boronic esters having the general structure (I) by the addition of a lithium dialkylamide (II) or other similar sterically-hindered strong base to a mixture of 1,1-dihaloalkane (III) and trialkyl borate (IV), also known as trialkoxyborane, in a suitable solvent such as tetrahydrofuran at a temperature in the range of from about 25.degree. C. to about -78.degree. C. or below. The subject process proceeds in accordance with the following reaction scheme: ##STR1## where R.sup.1 and R.sup.2, independently, are substituted or unsubstitued aliphatic groups, including but not limited to primary, secondary or tertiary alkyl groups, such as methyl, iisopropyl, cyclohexyl and the like, and where R.sup.1 and R.sup.2 may be the same or different and may be directly linked such that ##STR2## is a cyclic moiety such as 2,2,6,6-tetramethylpiperidide; where R.sup.3 is H or a lower primary, secondary or tertiary alkyl group; where R.sup.4, R.sup.5 and R.sup.6, independently, are substituted or unsubstituted aliphatic or aromatic groups, including but not limited to primary, secondary or tertiary alkyl groups, vinylic groups, allylic groups, benzylic groups and the like, and where the function substituents, if present, may comprise any substituents that will allow the formation of (VI), for example alkoxide, ether, ketal, or ester group; where R.sup.7 and R.sup.8 may be the same or different, and may be the same as R.sup.4, R.sup.5 and/or R.sup.6, or if hydrolysis or transesterification is carried out in the process scheme, may be H or any organic group that can form boronic esters; and where X is a halogen, particularly Br or Cl.
During the course of the reaction scheme, it is theorized that the unstable .alpha.,.alpha.-dihaloalkyl lithium compound (V) is generated and captured rapidly, before it has time to decompose, by the trialkyl borate (IV) to form an .alpha.,.alpha.-dihaloalkyl trialkoxyborate salt (VI). Treatment of the salt (VI) with an acid by any of several conventional procedures then yields the product, .alpha.,.alpha.-dihaloalkyl boronic ester (I).
Dichloromethyl boronic acid and some of its esters were first reported by Rathke et al., J. Organomet. Chem. Vol. 122, pp. 145-149 (1976). However, the dichloromethyl lithium required for the synthesis disclosed by Rathke et al cannot be prepared at temperatures much above -100.degree. C. because it decomposes rapidly at higher temperatures. Obviously, the expense of working at such cryogenic temperatures is prohibitive for industrial purposes and higher temperature processes were found to be necessary.
One such process, which is disclosed in Matteson et al, Organometallics, Vol. 2, pp 1529-1535 (1983), involves the generation of dichloromethyl lithium in the presence of pinacol butaneboronate at -78.degree. C., whereupon the dichloromethyl lithium is captured efficiently to form an .alpha.-chloro boronic ester, i.e., pinacol 1-chloropentylboronate. In U.S. Pat. No. 4,525,309 it was shown that the Matteson et al process could be carried out without the use of pinane butylboronate at 0.degree. C. to produce the analogous pinanediol 1-chloropentylboronate. However, the process disclosed in U.S. Pat. No. 4,525,309 was carried out using a different class of boron compounds having different reactivity, and involves a complex rearrangement process subsequent to the addition of the dichloromethyl group to the boron, which is not similar to the replacement of an alkoxy group by the dihalomethyl group as described in the present invention.
Brown et al, Organometallics, Vol. 2, pp 1316-1319 (1983), disclose the preparation of diisopropyl (dichloromethyl) boronate by essentially the same procedure as discussed above in connection with the Rathke et al article, but with an improved product isolation technique. As can be seen from the examples hereinbelow, the products prepared in accordance with the present invention can be isolated by the Brown et al technique, but such isolation is not, in and of itself, part of the present invention.
In another aspect, the present invention provides good yields of dihaloalkyl boronic esters even at temperatures as high as 0.degree. C., which is practical for industrial use, and measurable yields at temperatures as high as 20.degree.-25.degree. C.
The dihaloalkyl boronic esters prepared in accordance with the present invention, such as the achiral diisopropyl (dichloromethyl) boronate, are useful in intermediates for asymmetric synthesis. For example, Sadhu et al., Organometallics Vol. 3, pp 804-806 (1984), have shown that chiral 2,3-butanediol (dichloromethyl) boronates, which are easily prepared from the achiral diisopropyl (dichloromethyl) boronate, are useful for preparing chiral .alpha.-chloro boronic esters; whereas U.S. Pat. No. 4,525,309 indicates that chiral .alpha.-chloro boronic esters are useful intermediates for preparing the insect pheromones brevicomin (western pine beetle) and (3S-4S)-4-methyl-3-heptanol (European elm bark beetle).
It is to be understood that the one of the primary aspects of the present invention resides in the provision of a practical and efficient route for preparing dihaloalkyl boron compounds at temperatures on the order of 0.degree. C., thereby greatly reducing the inherent cost of producing these useful synthetic intermediates.